Alexander disease (AxD) is a rare, but devastating disease that affects neural development and causes ataxia, seizures, mental retardation, and many more. Previous studies have shown that specific nervous system cells called astrocytes are abnormal in AxD patients, which is caused by a mutation of glial fibrillary acidic protein (GFAP), a protein expressed exclusively in astrocytes within the brain. Astrocytes support both nerve cell growth and function, so the defects in AxD astrocytes are thought to lead to the nervous system defects. The over-expression and accumulation of this mutant protein leads to the formation of astrocytic inclusion bodies (Rosenthal fibers) that are present throughout the central nervous system in large numbers of AxD patients. Although genetic testing is available for AxD, it is significant to 3-dimensionally (3-D) assess various regional and global brain pathology and their clinical courses to identify multiple types of AxD, which would be a basis for a prediction of clinical courses and a better treatment for various types of AxD in the future. However, using non-invasive MRI techniques, detection of structural connections in abnormal white and gray matter remains elusive due to complex pathological phenomena that affect MRI contrast and diffusion properties of the pathologic regions. High-angular resolution diffusion MR imaging (HARDI) is useful to resolve complex fiber pathways in the brain, and we have recently further optimized this technique to resolve detailed coherent and crossing structures even in tissues with low fractional anisotropy which is useful to detect pathways through pathologic brain regions. In a radiological point of view, AxD can be a very important, informative model where we are able to test what exactly diffusion MRI tractography suggests us when interpreting clinical MRI findings of abnormal brain pathways. Diffusion MRI just measures the diffusivity of water molecules, and although there is a rough consensus what can be seen in healthy adult brains, there is still a great debate about what can be detected in pathologic brains using diffusion MRI. Although many studies conducted histological correlation of MR DTI, it is still unknown what can be seen in AxD with regional astrocytes abnormalities using diffusion MRI. To this end, in this R03, we propose to perform diffusion and structural MRI scans with histological confirmation on brains with AxD (infantile, juvenile, and adult forms) obtained from the University of Maryland Brain and Tissue Bank. We believe that our approach will be the first step to assess overall detailed pathology of the AxD brain, which can be useful for a greater understanding of AxD, and potentially for other protein aggregate disorders, for example Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.